Synthesis of ruscopine



United States Patent {3F RUSOJPM Benjamin Jaime Frydman, Boenos Aires,Argentina, assignor to Mathieson Chemical Corporation, New York, FLY acorporation of Virginia No Drawing. Filed lune 29, 1951, er. No. 120,4782 Claims. (Cl. 260-564) Ruscopine is a hypotensive agent actingprimarily through the ganglionic centers and thus can be used in thetreatment of conditions characterized by high blood pressure. Thisalkaloid has heretofore been obtained in relatively small proportions byextraction from plants of the species Carduus acamhoz'des as disclosedin copending application Serial No. 77,282, filed December 21, 1960.Ruscopine has the empirical formula C H N O and the structural formulaIt is an object of this invention to produce ruscopine synthetically inlarger quantities by more economic methods from simple known compoundsby a series of chemical steps.

According to this invention 3-(3,4-dimethoxy-phenyl)- propanol-l(prepared by reduction of 3,4-dimethoxydihydrocinnamic acid[3-(3,4-dimethoxy-phenyl)-propionic acid] with lithium aluminum hydride,and characterized through its 3,5-dinitrobenzoate) is treated with aphosphorus halide such as phosphorous tribromide to producel-halo-3-(3,4-dimethoxy-phenyl)-propane. A nitro group is introduced bytreatment with a metal nitrite, such as silver nitrite or an alkalimetal nitrite preferably the former, to producel-nitro-3-(3,4-dimethoxyphenyl propane.

Condensation of this compound with a lower alkyl acrylate such as methylacrylate gives the lower alkyl ester of racemic6-(3,4-dimethoxyphenyl)-4-nitrohexanoic acid, which, after purification,is treated with ammonia and the amide of said acid is obtained incrystalline condition. This amide is reduced to oily racemic1,4-diamino-6-(3,4- dimethoxy-phenyl)-hexane by reaction with lithiumaluminum hydride. This compound is the racemic form of adextro-rotatorybase obtained by hydrolysis of ruscopine with alkali and both have thesame Rf on paper chromatography. This identity is confirmed bypreparation of a crystalline N,N-dibenzoyl derivative from the racemicsynthetic diamine and from the dextro-rotatory natural1,4-diamino-6-(3,4-dimethoxyphenyl)-hexane, both of which give anidentical UV and IR spectra.

When the oily diamino base is treated with a lower alkyl imino ethersuch as ethyl formi-imidate, the amino groups are transformed intoamidines and the racemic form of ruscopine is obtained.

The racemic synthetic nlscopine is isolated as the dihydrochloride witha MP. 234-235" which, on paper chromatography, gives the same R asnatural ruscopine and with A max. 230 m (log e 4.50) and 284 m, (log4.17), which are the same maxima obtained from natural ruscopine. Theinfra red spectra are also identical.

The racemic mixtures may be separated into the respective isomers byconventional procedures.

The following examples are illustrative of the inven tion; alltemperatures are given in degrees centigrade.

EXAMPLE 1 V 3- (3,4-Dimeflz0xyphenyl )-Pr0pan0l-1 14 grams of3-(3,4-dimethoxyphenyl)-propionic acid are dissolved in 300 ml. ofabsolute ether and the solution added slowly to a Well stirredsuspension of 5 g. of

lithium aluminum hydride in 200 ml. ether. The tem perature increasesduring the addition and the ether boils. Boiling is continued for 3hours when the remaining lithium aluminum hydride is destroyed and then200 ml. of 20% sulfuric acid are added, resulting in a clear solution.The ethereal phase is separated and the lower aqueous phase is extractedthree times with 400 ml. each of ether. The ethereal extracts are unitedand evaporated, leaving an oily residue which is treated with 40 ml. of4 N sodium hydroxide. The resulting solution is extracted three timeswith 200 ml. of ether each time. The united extracts are evaporatedagain and the oily residue distilled in vacuum collecting the fractionboiling at 142l45 (0.5 mm.), which is redistilled and collected atl42l43 (0.5 mm.). 8 grams of a colorless oily liquid are obtained, withlow solubility in water, soluble in the usual organic solvents. Byacidification of the alkaline aqueous liquors, 3 grams of crude3-(3,4-dimethoxyphenyl)- propionic acid are recovered.

The 3-(3,4-dirnethoxyphenyl)-propanol-1 is characterized bytransformation into 3,5-dinitrobenzoate by mixing 1 ml. of the alcoholwith 2 ml. of pyridine, adding 1 g. of 3,S-dinitrobenzoyl-chloride,heating to dissolution and, when cool, pouring into 10 ml. of ice-water.A precipitate is formed, which, after filtering and recrystallizing from96% ethanol, is obtained as yellow needles melting at 106407.

Analysis.-Calculated for C H NO C, 55.38; H. 4.62; N, 7.17. Found: C,55.68; H, 3.87; N, 7.14.

EXAMPLE 2 1 -Nitr0-3- (3,4-Dimeth0xyphenyl) -Pr0pane 8 grams of the3-(3,4-dimethoxyphenyl)-propanol-1, prepared according to Example 1, aredissolved in 20 ml. of carbon tetrachloride and the solution cooled to35. 8 grams of phosphorous tribromide are added, keeping the solutioncool. It is then taken out of the ice bath and heated to boiling for 45minutes. 20 ml. of carbon tetrachloride are added and the solutionWashed with 5% sodium carbonate and then with water, dried andevaporated in vacuum to obtain an oil which is distilled collecting thefraction boiling at 128 (4 mm.). 4 grams of a colorless oil areobtained, insoluble in water, soluble in the usual organic solvents.

The oil is dissolved in 50 ml. of absolute ether, 4 g. of solid silvernitrite mixed with 4 g. of quartz, both of them finely ground, are addedand the mixture and the suspension shaken for two days at roomtemperature. The solid is then filtered and the ether evaporated,leaving an oily residue which is distilled collecting the fractionboiling 155l60 (2 mm.). This fraction is re distilled and 2.2 grams ofboiling point 158 (2 mm.) are collected. The product is an oily, lightyellow liquid, insoluble in water, soluble in N sodium hydroxide, thesolution taking an orange color. Soluble in the usual organic solvents.

Analysis.Calculated for C l-l NO r C, 58.65; H, 6.71; N, 6.22. Found: C,58.71; H, 6.67; N, 6.02.

EXAMPLE 3 Analysis.Calculated for -C H NO N, 4.50. Found: N, 4.40.

EXAMPLE 4 6- (3 ,4-Dimethxy phenyl -4-N itro-H exanoamide 1 gram of thenitro ester described in Example 3 is added with stirring to 20 ml. ofmethanol saturated with ammonia, leaving the mixture for 48 hours at 5.It is then evaporated to dryness and the solid residue recrystallizedseveral times from ethanol 70%. 200 mg. of white prisms M.P. 38.39 areobtained. With a low solubility in water and ethyl ether, they are moresoluble in methanol, ethanol, benzene and chloroform.

Analysis.-Calculated for C I-1 N 0 C, 56.76; H, 6.75; N, 9.46. Found: C,56.56; H, 6.75; N, 9.41.

EXAMPLE 5 1,4-Diamino-6-(3,4-Dimeth0xyphenyl) -Hexane 200 mg. of theamide described in Example 4 are dissolved in ml. tetrahydrofurane andthe solution slowly added to a suspension of one gram of lithiumaluminum hydride in 20 ml. of the same solvent. After the addition, themixture is boiled for 7 hours with good stirring. The excess of lithiumaluminum hydride is decomposed by adding 100 ml. of 10% water solutionof sodium and potassium tartrate.

The diamine is extracted with ether employing Mayers reaction to controlthe extraction. 100 ml. of ether are employed three times for thisextraction. The united ethereal extracts are evaporated yielding 100 mg.of a white oil. This oil on paper chromatography with thesolvent-described below, gives an Rf (0.09) identical to that obtainedemploying the diamine prepared by alkaline hydrolysis of the alkaloidruscopine from C. acanthoides. (For determiningthe Rf, descendingchromatography is employed with Whatman No. 1 paper. The normal phase isnormal butanol saturated with buffer pH 5.6 (acetic acid-sodiumacetate). For development of the chromatogram Dragendorif reagent isemployed.)

The diamine is characterized by benzoylation to obtain 1,4dibenzoylarhino-G-(dimethoxyphenyl)-hexane, the preparation of thiscompound being carried out in the following way:

The 100 mg. of oily diamine obtained in one of the preparations isdissolved in 1 ml. pyridine and 2 ml. benzene. The solution was cooledto 0-5 and 0.2 m1. of benzoyl chloride added. After the addition themixture is allowed to reach room temperature and slowly heated to 70 for30 minutes. 20 ml. of water are then added and the benzene phase isseparated and the water solution extracted with benzene several times.

- The united benzene extracts are washed with 5% sodium carbonatesolution, with water and then well dried and evaporated. The residue isrecrystallized several times from ethanol giving 70 mg. of prisms M.P.134- 135 A max. 284 m (log 5 5.17) in ethanol.

The UV spectrum is identical with that given by the dextro-rotatory(+)1,4 dibenzoylamino-6-(3,4 dimethoxyphenyl)-hexane prepared bybenzoylation of the base obtained by alkaline hydrolysis of the alkaloidruscopine isolated from C. acanthoz'des which has an M.P. 127-128.

The infra-red spectrum of the synthetic and the dextrorotatory compoundare also identical when taken in a chloroform solution.

EXAMPLE 6 (i) Ruscopine 30 mg. of crude1,4-diamino-6-(3,4-dimethoxyphenyl)-hexane prepared as described inExample 5 are dissolved in 10 ml. dried ether and treated at roomtemperature with 10 ml. of an ethereal solution containing the ethylformi-imidate obtained from 100 mg. of ethyl formi-imidatehydrochloride. The new solution is left for 10 days at ambienttemperature and then evaporated to dryness, the residue is dissolved in0.5 ml. of 96% ethanol and concentrated hydrochloric acid added to pH 2.By cooling the solution to 0 and leaving at this temperature for severalhours, crystals of (i) ruscopine hydrochloride precipitate. Thehydrochloride is recrystallized from ethanol 96 when needles M.P. 234235are finally obtained.

This salt on paper chromatography has Rf 0.11, in the same systemdescribed in Example 5. It gives a UV spectrum with A max. 230 my (log6, 4.50); 284 m (log a, 4.17) qualitative and quantitatively identicalwith the UV-spectrum of the hydrochloride of the natural alkaloidruscopine prepared from C. acanthoides which has an M.P. 249-25 1 andgives also, the same R on paper chromatography.

What is claimed is:

1. A process for the production of ruscopine which comprises brominating3 (3,4 dimethoxyphenyl) propanol-l, to obtain1-brorno-3-(3,4-dimethoxyphenyl) pro pane, reacting the last namedcompound with a metal nitrite selected from the group consisting ofsilver nitrite and alkali metal nitrite to obtain1-nitro-3-(3,4-dimethoxyphenyl)propane, condensing the last namedcompound with a lower alkyl aer'ylate to obtain the lower alkyl ester of6-(3,4-dimethoxyphenyl)-4-nitrohexanoic acid, amidating said acid toobtain 6-(3,4-dimethoxyphenyl)-4-nitrohexanoamide, reducing said amideto obtain 1,4 diamino 6 (3,4-dimethoxyphenyl)hexane and and reacting thelast named compound with a lower alkyl imino ether to obtain ruscopine.

2. A process for the production of ruscopine which comprises reacting3-(3,4-dimethoxyphenyl) propanol-l with phosphorus tribromide to obtainl-bromo-3-(3,4-dimethoxyphenyl) propane, reacting the last namedcompound with silver nitrite to obtainl-nitro-3-(3,4-dimethoxyphenyl)p'ropane, condensing the last namedcompound with methyl acrylate to obtain the methyl ester of6-(3,4-dimethoxyphenyl)-4-nitrohexanoic acid, amidat ing said acid withammonia to obtain 6-(3,4-dimethoxyphenyl)-4-nitrohexanoamide, reducingsaid amide with lithium aluminum hydride to obtain l,4-diamino-6-(3,4-dimethoxyphenyl)hexane and reacting the last named compound with ethylimino ether to obtain ruscopine.

References Cited in the file of this patent UNITED STATES PATENTS GreatBritain June 12, 1939 OTHER REFERENCES Flory: Principles of PolymerChemistry, (New York, 1953), pp. 43 and 89.

Adams et al.: Organic Reactions, vol. VI, pp. 470 506 (1951).

Wagner et al.: Synthetic Organic Chemistry, pp. 91, 568 and 749 (1953).

.Migrdichian: Organic (1957).

Synthesis, pp. 404-406

1. A PROCESS FOR THE PRODUCTION OF RUSCOPINE WHICH COMPRISES BROMINATING3 - (3,4 - DIMETHOXYPHENYL) PROPANOL-1, TO OBTAIN1-BROMO-3-(3,4-DIMETHOXYPHENYL) PROPANE, REACTING THE LAST NAMEDCOMPOUND WITH A METAL NITRITE SELECTED FROM THE GROUP CONSISTING OFSILVER NITRITE AND ALKALI METAL NITRITE TO OBTAIN1-NITRO-3-(3,4-DIMETHOXYPHENYL)PROPANE, CONDENSING THE LAST NAMEDCOMPOUND WITH A LOWER ALKYL ACRYLATE TO OBTAIN THE LOWER ALKYL ESTER OF6-(3,4-DIMETHOXYPHENYL)-4-NITROHEXANOIC ACID, AMIDATING SAID ACID TOOBTAIN 6-(3,4-DIMETHOXYPHENYL)-4-NITROHEXANOAMIDE, REDUCING SAID AMIDETO OBTAIN 1,4 - DIAMINO - 6 - (3,4-DIMETHOXYPHENYL)HEXANE AND ANDREACTING THE LAST NAMED COMPOUND WITH A LOWER ALKYL IMINO ETHER TOOBTAIN RUSCOPINE.